Introduction

What if a person at risk of HIV infection could start taking preventative medications on a regular basis before being exposed to HIV to reduce their risk of infection?

This strategy, known as pre-exposure prophylaxis (or PrEP), is beginning to show promise in research studies and could potentially provide another much needed prevention option for those at risk of infection. Despite its promise, this strategy raises a number of concerns and -- if we aren't prepared -- its introduction could end up doing more harm than good.

PrEP to Prevent HIV Infection

PrEP refers to the use of a medication before an exposure in order to prevent a disease or a condition. For example, medications are commonly used to prevent malaria, tuberculosis and pregnancy.

PrEP to prevent HIV infection would use the same anti-HIV medications as those used to treat people who are HIV-positive. To reduce the risk of infection of HIV-negative individuals, anti-HIV medications would need to be taken on a regular basis both before and after a potential exposure.

This strategy should not be confused with post-exposure prophylaxis (or PEP), which is the use of antiretrovirals after a potential exposure for a limited period of time (28 days).

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The Different Flavours of PrEP

PrEP is one of the most promising biomedical HIV prevention tools in development and is beginning to garner the attention of the media. Headlines such as "A pill a day to keep HIV away" or "Will a pill a day keep HIV at bay?" are catchy but they don't tell the whole story. Taking an anti-HIV pill daily is one possible way PrEP could be used, but it's not the only strategy in development.

In addition to a pill taken orally, the anti-HIV medications used for PrEP could be available in a variety of forms, such as a gel applied topically to the vagina or rectum, a ring inserted into the vagina, or an injection. Researchers are also looking into different dosing schedules, including the use of anti-HIV drugs daily, intermittently (once or twice a week) or coitally (before and after sex).

The Changing Terminology: Microbicides as a Form of PrEP

To those who know what a microbicide is, a gel applied to the vagina or rectum may sound very familiar. A microbicide is an experimental strategy that would involve applying a product -- such as a gel, film or suppository -- into the vagina or rectum to block HIV infection. Although the idea is simple enough, it has been difficult for researchers to figure out what needs to be put in a microbicide for it to work.

Early microbicides contained a variety of chemicals that all failed to reduce the risk of HIV transmission. After several studies produced disappointing results, researchers were forced to re-consider what they were putting into their microbicides and now the majority of newer microbicides in development contain anti-HIV medications.

Microbicides and PrEP are often referred to as distinct prevention strategies but newer microbicides that contain anti-HIV drugs fall under the definition of PrEP -- the use of medications before a potential exposure to prevent a disease. Recognizing medication-based microbicides as a form of PrEP is important because the use of anti-HIV drugs in HIV-negative individuals, whether in pill or gel form, raises cross-cutting concerns, which are the main focus of this article and are discussed later.1

What Is Being Researched?

Although many PrEP strategies are being researched, only a few are in the latter stages of development, including:

Anti-HIV pills that contain (a) the drug tenofovir alone or (b) tenofovir in combination with emtricitabine, to be taken every day

Vaginal gels that contain tenofovir alone, to be used every day or before and after sex

These strategies are being researched in a variety of populations, including men who have sex with men, injection drug users, heterosexual serodiscordant couples and heterosexual women. These studies are nearing completion and the results are expected by 2013.

Unfortunately, we won't know in the near future if all types of PrEP will work. Some important PrEP strategies are at the earlier stages of development or lack funding. Therefore, information on their effectiveness may not be available for many years. These strategies include:

Anti-HIV gels used in the rectum

Anti-HIV pills taken occasionally or before and after sex

Long-lasting injections and intravaginal rings that would only need to be used once a month

What Evidence Is Available So Far -- Does PrEP Work?

In 2010, two studies released exciting results showing that two different PrEP strategies -- (1) a gel applied vaginally before and after sex and (2) a pill taken daily -- were able to reduce the risk of HIV infection when used by certain populations.

CAPRISAThe first evidence that PrEP may work was announced in the summer of 2010, at the International AIDS Conference in Vienna.2 For this medium-sized study, known as CAPRISA 004, female participants were asked to apply a 1% tenofovir gel into the vagina before and after sex. The study found that the tenofovir gel was safe, well tolerated and reduced the overall risk of HIV infection in women by 39%. Among women who used the gel more consistently (for more than 80% of their sex acts), the level of protection was higher than 50%. (For more on CAPRISA see PrEP -- hope and excitement greet first successful microbicide.)

iPrExA few months later, at the end of November 2010, the results of a study called iPrEx were announced: a pill containing tenofovir and emtricitabine taken daily reduced the risk of HIV infection among men who have sex with men.3 The overall reduction in HIV incidence was 44% and, similar to the CAPRISA study, men who adhered more consistently to the pill-taking schedule had a higher level of protection. Those men who adhered more than 90% of the time had a 73% reduction in risk of HIV infection. (For more on iPrEx see Truvada for HIV prevention -- some good news but caution is still needed.)

While the results of these studies are promising and show that anti-HIV medications used consistently before and after an exposure can reduce the risk of HIV infection, we still need additional studies to confirm these results before regulatory approval is possible. Research studies currently underway that are investigating PrEP in other populations will tell us more about the effectiveness of these PrEP strategies when used to protect against other routes of HIV transmission.

Partial Protection -- A Cause for Concern

From a quick look at the available evidence, we can see that it's unlikely that PrEP will be highly protective against HIV infection. The PrEP strategies investigated in both the iPrEx and CAPRISA studies provided only moderate protection against HIV and infections still occurred among people using PrEP (even in those who consistently adhered to their medication schedule -- taking a pill every day or applying a gel before and after sex).

Partially protective prevention tools raise several issues. One major concern is the possibility that people using PrEP will engage in more risk behaviours because they falsely believe that they are highly protected against HIV infection. It will be important to develop accurate messaging about the level of protection PrEP provides so people using PrEP can make informed decisions related to their risk-taking behaviours. Partial protection is a potentially challenging concept to communicate and understand. The level of protection provided by PrEP will also influence important decisions made by regulatory authorities and public health agencies related to PrEP access, such as if and when PrEP will become available, who will get it, and how much it will cost.

Our lack of previous experience with partially protective tools may mean that we are unprepared to address these challenges and decisions. Moderately protective tools are uncommon in disease prevention and many of the technologies available to prevent diseases other than HIV, such as childhood vaccines, are highly effective and often provide close to 100% protection. Strategies that are currently available to prevent HIV infection, particularly those that help someone avoid exposure in the first place -- such as condoms, clean needles, HIV testing and reducing the number of sexual partners -- are also highly protective if used consistently.

Because of this partial effectiveness, PrEP will only be beneficial if it does not replace condom use. However, PrEP could reduce HIV infections if it is made available to individuals who are not otherwise willing or able to use condoms. We all know that there are lots of reasons why people don't use condoms either through choice or lack of choice.

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